Interaction of innate and adaptive immunity leads to alloimmune responses that may be detrimental to cardiac allografts and heart transplant recipients. Antigen-presenting cells (APC) initiate allorecognition by processing foreign peptides, migrating to secondary lymphoid tissue, and presenting these peptides to recipient lymphocytes. After recognition, alloreactive T lymphocytes proliferate and migrate to their target tissue. Although the current immunosuppressive regiments effectively inhibit the proliferation of alloreactive T lymphocytes, they have several metabolic, infectious, renal and malignant side-effects. In addition, the long-term survival of heart transplant patients is decreased by gradual concentric intimal thickening of large and small allograft coronary arteries—cardiac allograft arteriosclerosis—despite the use of modern immunosuppression.
The lymphatic network forms a conduct system that transfers interstitial fluids and inflammatory cells from the target tissue to secondary LN, and is essential in the activation of adaptive immunity. Vascular endothelial growth factor C (VEGF-C) and its receptor VEGFR-3 are the key regulators for lymphatic growth. VEGF-C is essential in the development and maintenance of the lymphatic system, and improper lymphangiogenesis is related to many pathological conditions. Lymphatic vascular insufficiency leads to lymphedema, whereas extensive lymphangiogenesis is often seen in tumor metastasis and inflammatory situations. During inflammation, macrophages are a rich source for VEGF-C, and pro-inflammatory cytokines such as TNF-α, IL-1α and -β(15) as well as TGF-β (16) induce VEGF-C expression. Dendritic cells (DC) may express VEGFR-3 during inflammation (Hamrah et al., (2003), Am J. Pathol., 163: 57-6817) which renders them responsive for VEGF-C-induced migration (Chen et al., (2004), Nat. Med., 10: 813-81518). Also, lymphatic endothelial cells (EC)—in contrast to vascular EC—secrete CCL21 chemokine that mediates CCR7+ inflammatory cell traffic to lymphoid organs and peripheral effector sites. (See Kriehuber et al., (2001), J. Exp. Med., 194: 797-808; Saeki et al., (1999), J. Immunol. 162: 2472-2475; Campbell et al., (1998), J. Cell. Biol. 141: 1053-1059; and Lo et al., (2003), J. Clin. Invest. 112: 1495-1505.
Corneal transplant is currently the most successful tissue transplantation procedures in humans, with a first year survival rate as high as 90%, even in the absence of routine HLA tying and with minimal immunosuppressive therapy. The healthy cornea is generally a non-vascular tissue. DeVries, U.S. Patent Publication No. 2003/0180294 purports to describe use of a VEGFR-3 inhibitor to reduce lymhangiogenesis in a transplanted cornea to extend its survival. Chen et al., (2004), Nat. Med., 10: 813-81518, purport to describe that blockade of VEGFR-3 in corneal transplants suppresses corneal antigen presenting dendritic cells, delaying rejection of corneal transplants. The same research group previously reported that dendritic cells in the cornea were VEGFR-3+, whereas similar dendritic cells were absent in the skin, even though the cornea shares embryological origins with the skin.
A need exists for all transplanted tissues and organs, especially vascularized tissues and organs, for new materials and methods for slowing, reducing, or eliminating rejection and also for slowing, reducing, or eliminating graft arteriosclerosis.